bims-minfam 2023-06-04 papers

Issue of 2023–06–04
six papers selected by
Ayesh Seneviratne, Western University

J Nutr Health Aging. 2023 ;27(5): 312-313

Editorial: Obesity and Accelerated Aging.

Through shared pathophysiologic mechanisms, obesity exacerbates the age-related decline in physical function, which leads to frailty and disability. Obesity and aging are characterized by chronic low-grade inflammation, which contributes to reduced muscle quality and protein control mechanisms as well as to diminished muscle anabolic response. Obesity causes oxidative stress and inflammation, which increases telomere shortening. Calorie excess increases ROS formation, which damages nucleus, endoplasmic reticulum, and mitochondria and promotes cellular senescence. Given the persistence of DNA damage associated with altered DNA repair proteins in obesity and aging, it is thought that inability to repair DNA may be the principal molecular event that underlies accelerated aging. Calorie restriction in combination with exercise slows biological aging by protecting against the molecular and cellular damages that occur in obesity and aging. Promising approaches such as Time Restricted Eating, Mediterranean Diet, and Senolytics need further investigation.

DOI: https://doi.org/10.1007/s12603-023-1922-0

Cell Stem Cell. 2023 Jun 01. pii: S1934-5909(23)00174-1. [Epub ahead of print]30(6): 781-799.e9

Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils.

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.

Keywords: CRISPR; TET2; clonal hematopoiesis; hematopoietic stem and progenitor cells; immune system; preleukemic neutrophil

DOI: https://doi.org/10.1016/j.stem.2023.05.004

Neurosci Bull. 2023 May 31.

Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases.

Feifei Li, Chou Wu, Gelin Wang.

As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.

Keywords: Ageing; NAD metabolism; Neurodegenerative diseases; Neuroprotection; Therapeutic strategy

DOI: https://doi.org/10.1007/s12264-023-01072-3

Oxf Open Immunol. 2023 ;4(1): iqad004

The ageing immune system as a potential target of senolytics.

Peter Yandi Du, Ankesh Gandhi, Manraj Bawa, Justyna Gromala.

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.

Keywords: ageing; immune system; senescence; senolytic; therapy

DOI: https://doi.org/10.1093/oxfimm/iqad004

BMC Cancer. 2023 Jun 02. 23(1): 498

How frail is frail in oncology studies? A scoping review.

James A Fletcher, Benignus Logan, Natasha Reid, Emily H Gordon, Rahul Ladwa, Ruth E Hubbard.

AIMS: The frailty index (FI) is one way in which frailty can be quantified. While it is measured as a continuous variable, various cut-off points have been used to categorise older adults as frail or non-frail, and these have largely been validated in the acute care or community settings for older adults without cancer. This review aimed to explore which FI categories have been applied to older adults with cancer and to determine why these categories were selected by study authors.
METHODS: This scoping review searched Medline, EMBASE, Cochrane, CINAHL, and Web of Science databases for studies which measured and categorised an FI in adults with cancer. Of the 1994 screened, 41 were eligible for inclusion. Data including oncological setting, FI categories, and the references or rationale for categorisation were extracted and analysed.
RESULTS: The FI score used to categorise participants as frail ranged from 0.06 to 0.35, with 0.35 being the most frequently used, followed by 0.25 and 0.20. The rationale for FI categories was provided in most studies but was not always relevant. Three of the included studies using an FI > 0.35 to define frailty were frequently referenced as the rationale for subsequent studies, however, the original rationale for this categorisation was unclear. Few studies sought to determine or validate optimum FI categorises in this population.
CONCLUSION: There is significant variability in how studies have categorised the FI in older adults with cancer. An FI ≥ 0.35 to categorise frailty was used most frequently, however an FI in this range has often represented at least moderate to severe frailty in other highly-cited studies. These findings contrast with a scoping review of highly-cited studies categorising FI in older adults without cancer, where an FI ≥ 0.25 was most common. Maintaining the FI as a continuous variable is likely to be beneficial until further validation studies determine optimum FI categories in this population. Differences in how the FI has been categorised, and indeed how older adults have been labelled as 'frail', limits our ability to synthesise results and to understand the impact of frailty in cancer care.

Keywords: Deficit accumulation; Frail elderly; Frailty; Frailty index; Geriatric assessment; Geriatric oncology

DOI: https://doi.org/10.1186/s12885-023-10933-z

BMC Geriatr. 2023 05 30. 23(1): 334

Frailty in chronic myeloid leukemia: evidence from 2016-2018 Nationwide Inpatient Sample of the US.

Lin Huan-Tze, Liu Yun-Ru, Lee Kuan-Der, Tzeng Huey-En.

BACKGROUND: Frailty is a marker of poor prognosis in older adults with hematologic malignancies and contributes to the severe vulnerability of the aging population to adverse health outcomes. This study aimed to determine the association between frailty and outcomes in hospitalized patients with chronic myeloid leukemia (CML).
METHODS: The International Classification of Diseases (ICD-10) identified data on hospitalized patients 20 years or older admitted with CML between 2016 and 2018 in the US National Inpatient Sample (NIS) database. The cohort was further divided into groups of patients with or without frailty. Logistic regression analysis was performed to determine associations between study variables and clinical outcomes. A stratified analysis of the association between frailty and in-hospital mortality by age group was also performed.
RESULTS: A total of 13,849 hospitalized patients with CML were included, 49.6% of whom had frailty. The mean age of the patients was 65.1 years, and 7,619 (56.2%) of them were male. Frailty was associated with nearly 4 times the risk of in-hospital mortality, 3 times the risk of unfavorable discharge, 3 times the risk of prolonged LOS,, and significantly more in total hospital costs. In addition, frailty was associated with a significantly increased risk of in-hospital mortality in all age subgroups (< 40 years, 40-59 years, and > 60 years) compared with no frailty.
CONCLUSIONS: Frailty strongly predicts poor clinical outcomes in US patients with CML.

Keywords: Chronic myeloid leukemia (CML); Frailty; In-hospital outcome; Nationwide Inpatient Sample (NIS)

DOI: https://doi.org/10.1186/s12877-023-03962-7